Benzodiazepine intermediates



Jan. 20, 1970 s. c. BELL BENZODIAZEPINE NTERMEDIATES original Filed may2s, 1964 All! o l mrowoNrQLaz nroworowrz o c L. L my www Wm m A` www Y Bo O\ nro@ Nomowrowzz United States Patent O 3,491,138 BENZODIAZEPINEINTEDIATES Stanley Charles Bell, Penn Valley, Pa., assignor to AmericanHome Products Corporation, New York, N JY., a corporation of DelawareOriginal application .lune 26, 1964, Ser. No. 378,345, now Patent No.3,328,397, dated .lune 27, 1967. Divided and this application Sept. 22,1966, Ser. No. 581,229 Int. Cl. C07c 143/68; C07d 87/00 U.S. Cl.260--456 4 Claims ABSTRACT F THE DISCLOSURE A process for preparingacyloxyacetamidobenzophenones useful as intermediates in the preparationof benzodiazepin-Z-ones which are active as anti-convulsants, sedatives,and muscle relaxants utilizing anthranilic acid as the starting materialis described. Anthranilic acid is converted toN-acyloxyacetylanthranilic acid, the product is cyclized and thentreated with one equivalent of aryl Grignard reagent.

This application is a division of co-pending application Ser. No.378,345 led June 26, 1964, now U.S. Patent No. 3,328,397.

This invention relates to processes for making compositions of matterclassified in the art of chemistry as substituted 2-aminophenyl arylketones and to intermediates for making them.

The invention sought to be patented in its principal process aspectresides in the concept of converting a 2-acyloxymethyl-4H-3,l-benzoxazin-4 one to 2 acyloxyacetamidobenzophenoneby mixing an aryl magnesium halide with the -benzoxazin-4-one dispersedin a liquid medium inert to the reactants and hydrolyzing the resultingaddition product.

The invention sought to be patented in a further process aspect residesin the concept of a sequence of reactions including: converting ananthranilic acid to an N-acyloxyacetylanthranilic acid by acylation withacyloxyacetyl halide, cyclizing the product so obtained in the presenceof a dehydrating agent to form a2-acyloxymethyl-4H-3,1-benzoxazin-4-one, and converting said 4H-3,1-benzoxazin-4-one to 2-acyloxyacetamidophenyl aryl ketone by additionof an aryl magnesium halide.

The invention sought to be patented in a principal composition aspect,is described as residing in the concept of a chemical compound having amolecular structure in which there is attached to the N-atom ofanthranilic acid an acetoxyacetyl radical, or phenylsulfonoxyacetylradical.

The tangible embodiments of the compositions of this aspect of theinvention possess the inherent general physical properties of being highmelting, white crystalline solids, are substantially insoluble in water,and are soluble in polar solvents, such as lower aliphatic alcohols.Examination of these compounds produced according to the hereinafterdescribed process reveals upon ultraviolet and infrared spectrographicanalysis, spectral data confirming the molecular structure hereinbeforeset forth.

Thus the is evident. The aforementioned physical characteristics, takentogether with the nature of the starting materials, and the mode ofsynthesis, positively confirm the structure of the compositions soughtto be patented.

The invention sought to be patented in a further composition aspect, isdescribed as residing in the concept of a chemical compound having amolecular structure in which the 4H-3,1benzoxazin4one nucleus hasattached, to the 2-position, the acetoxymethyl radical, or aphenylsulfonoxymethyl radical.

The tangible embodiments of these compositions of the invention possessthe inherent general physical properties of being relatively highmelting, while crystalline solids, are substantially insoluble in waterand are soluble in polar solvents, such as lower aliphatic alcohols.Examination of the compounds produced according to the hereinafterdescribed process reveals upon ultraviolet and infrared spectrographicanalysis spectral data confirming the molecular structure hereinbeforeset forth. Thus the internal 0 Il O and -N=C- are evident. Theaforementioned physical characteristics, taken together with the natureof the starting materials and mode of synthesis, positively confirm thestructure of the compositions sought to be patented.

The tangible embodiments of the invention possess the inherent applieduse characteristics of being intermediates for the production ofvaluable 2-hydroxyaminoacetamidobenzophenones, disclosed in copendingU.S. applications, Ser. No. 283,966 and Ser. No. 283,967, both filed May29, 1963, both now abandoned, useful for the production of1,3-dihydro-5-phenyl-2H-1,4-benzodiaZepin-2 ones which are valuable forhuman and medicinal uses having demonstrated activity asanti-convulsants, sedatives, and musclerelaxants, according to standardpharmacological test procedures.

As used herein, the term acyl means a radical derived from an organicacid having only one active hydrogen atom, by removal of the hydroxygroup, i.e., removal of said hydrogen and the oxygen atom to which it isattached, including but without limiting the generality of theforegoing, saturated and unsaturated alkanoyl such as acetyl caproyl,aroyl such as benzoyl, naphthoyl, substituted benzoyl, araliphaticcarbonyl such as cinnamoyl, heterocyclic carbonyl such as furoyl,pyridinoyl, the corresponding sulfonic acid acyl and the like.

The process of making in the manner of using the inventions will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

The new processes of my invention and the manner of using thecompositions produced thereby, are illustrated schematically for aspecific embodiment thereof in FIGURE 1, to which the Roman numerals inparenthesis in the following description refer.

The starting materials for the processes of my invention are generallyknown or are prepared by procedures which are well known to those withordinary skill in the art of organic chemistary.

Treatment of an anthranilic acid (I) suspended in solvent such aschloroform or dissolved in a solvent such as dimethoxyethane with anacyloxyacetyl halide such as the chloride or bromide, produces anN-acyloxyacetylanthranilic acid (II) (VI). Since the reaction isexothermic, the addition is performed dropwise and its rate regulated topermit a gentle reflux of the solvent. Reuxing is continued until theliberation of hydrogen chloride or hydrogen bromide, depending on whichacyloxyacetyl halide was used, is complete. The reaction is thenpermitted to cool and the precipitated product is separated andrecrystallized.

The N-acyloxyacetylanthranilic acid so produced, is heated in admixturewith an excess of the dehydrating agent such as an acid anhydride,preferably acetic anhydride, until a clear solution results. Onconcentration of the reaction mixture to approximately 1/2 its volumeand cooling the product 2acyloxymethyl4H-3,1benzoxazin 4-one (III) (VII)precipitates.

When a suspension of this product is suspended in anhydrous ether and anaryl magnesium bromide, such as phenylmagnesium bromide, is addeddropwise, with stirring and chilling, I have discovered that,surprisingly, while two points are initially present for reaction,namely, an external ester and an internal ester, the reaction occursselectively at the internal ester provided only one equivalent of theGrignard reagent is added. Since the reaction does not occur attheexternal ester Ibut occurs predominantly at the ring ester group, ringopening occurs and there is produced, a 2acetamidobenzophenone. (IV)(VIII) Ether is the preferred medium for the reaction; however, anymedium in which the Grignard reagent is nonreactive can be used. Thereaction mixture is stirred at room temperature for approximately 30minutes after the addition of the Grignard reagent is complete in orderto insure optimum yields. It is then decomposed with excess acid,preferably hydrochloric acid. The ether layer containing the reactionproduct is separated, partially concentrated under vacuum and chilled toprecipitate the product.

The 2-acy1oxyacetamidobenzophenone so obtained is suspended in ethanol.Addition of sodium hydroxide or other alkali metal hydroxide solutionwith stirring permits hydrolysis to occur. While hydrolysis could occureither at the ester linkage or at the amide linkage, selectivehydrolysis at the ester occurs to produce 2-hydroxyacetamidobenzophenone(IX). On removal of the medium under vacuum, and recrystallzation of theresulting precipitate from a medium such as alcohol, the product isobtained in optimum yield.

The Z-hydroxyacetamidobenzophenone (V) so produced is then converted toZ-phenylsulfonoxyacetamidobenzophenone (VIII) by -dissolving it in asolvent such as triethylamine and adding an arylsulfonyl halide such asfor example, the chloride ,or the bromide. To permit reaction to go tocompletion, the reaction mixture is warmed on a steam bath forapproximately 30 minutes. On cooling and diluting with ice water, theproduct precipitates out. It may be purified by recrystallization from apolar solvent such as acetonitrile.

Alternatively, anthranilic acid, suspended in a solvent such aschloroform, or dissolved in a solvent such as dimethoxyethane, can beconverted to N-phenylsulfonoxyacetylanthranilic acid by the addition lofa phenylsulfonoxyacetyl halide, such as the chloride or the bromide.Retluxing and stirring are continued until evolution of the hydrogenchloride or bromide, depending on the halide used, is complete.

Ring closure to the benzoxazin-4-one is carried out in a manner similarto that described above more ygenerally for acyloxyacetylanthranilicacid.

Addition of a Grignard reagent to aZ-phenylsulfonoxymethyl-4H-3,1-benZoxazin-4-one, or in the more generalsituation, namely addition of a Grignard reagent to 2- acyloxymethyl 4H3,1-benzoxaZin-4-one, as described above, could occur either at theinternal ester or the external ester or both producing a reactionproduct mixture difficult to purify. I have discovered, however thatunder controlled reaction conditions, particularly with respect to theamount of Grignard reagent added, reaction occurs predominantly with theinternal ester, forming in good yield2-phenylsulfonoxyacetamidobenzophenone.

The sulfonoxyacetamidobenzophenone so obtained is used for producing theValuable and useful hydroxyaminoacetamidobenzophenones (IX), bydissolving it in a solvent such as methyl Cellosolve, heating it toapproximately 85 C., and adding a solution ,of hydroxylaminehydrochloride and water containing sodium hydroxide. The temperature ismaintained at approximately 85-90" C. for about minutes. On cooling anddilution with water the product precipitates.

The anthranilic acids employed as starting materials for conducting ourprocesses are known or are readily prepared by procedures known to thoseskilled in the art.

It will be apparent from the disclosure herein to those skilled in theart of organic chemistry that for the purposes of this invention certainof the carbon atoms of the anthranilic acids employed as startingmaterials can be substituted with groups which do not interfere with thesubsequent reactions. Thus, the presence of groups such as halogen,alkyl, or alkoxy will not interfere under the hereinbefore describedconditions and will be present unchanged in a corresponding position inthe iinal pro-duct. It will also be apparent to those skilled in the artof organic chemistry that for the purposes of this invention certain ofthe carbon atoms of anthranilic acid employed as starting materials canbe substituted with groups as for example hydroxy, or hydroxyalkyl whichadd Grignard reagent during the course of the hereinbefore reactions butremain otherwise unchanged and revert to their original identity onhydrolysis of the addition product. The presence ,of such groups willnot interfere with the subsequent reactions provided an equivalentexcess of Grignard is employed.

Further it will be apparent to those skilled in the art of organicchemistry that for the purposes of this invention certain of the carbonatoms of the anthranilic acids employed as starting materials canbesubstituted with groups as for example an aldehyde or ketone, whichgroups react with Grignard reagent during the course of the hereinbeforereactions and which property can be utilized to change the saidsubstituent under the reaction conditions to correspondingly differentsubstituents, eg. alcohols merely by using the appropriate equivalentexcess of Grignard reagent.

From the disclosure herein, illustrating the invention as applied toaryl Grignard reagents, which produce benzophenone, it will be apparentto organic chemists that other aryl nuclei can be used in lieu of phenylprovided the Grignard reagents can be prepared, without effecting thecourse of the subsequent reactions. Accordingly, such reactions whereinthe phenyl group is replaced by the cyclic groups which will form aGrignard reagent such as Z-thienyl are the full equivalent of theinvention as particularly claimed.

When the starting compounds are substituted as hereinbefore recited, itwill be apparent herefrom to those skilled in the art of chemistry, thatthe intermediate compounds and the nal products formed by the processesof invention will bear, correspondingly, the same substituents.

It will also be apparent to those with ordinary skill in the art oforganic chemistry that the acyl group except in the case where it is asulfonyl group only serves a pro# tecting function and therefore can beany acyl group which does not interfere with the subsequent reactions.

Similarly, the aryl group of the arylmagnesium halide used for thesubsequent condensation to form the substituted aryl ketone, can besubstituted with groups such as halogen, alkyl, or alkoxy which do notinterfere with the further reactions involving the atom at the2-position of the starting anthranilic acid, and these groups will bepresent unchanged in a coresponding position in the nal product.Therefore, in the processes of the invention, except for any limitationexpressed in this specication, all anthranilic acids containingnon-interfering groups can be employed as starting materials in theprocess of making aspects of this invention. In like manner, in the2-acetoxyacetamidoanthranilic acids or the 2-phenylsulfonoxyacetamidoanthranilic acids of my invention, the aryl ring can be substituted. Theacyloxyacetamidobenzophenones andy the hydroxyacetamidobenzophenones,formed as intermediates, can be substituted at the acetamido nitrogenwith hydrogen, or the hydrogen may be replaced subsequent to theformation of the aryl ketone, with an alkyl group such as methyl, ethyl,isopropyl, alkenyl group such as allyl and methallyl or a lower aralkylgroup such as benzyl or phenethyl.

The phenyl group of the anthranilic acid and the aryl group laterintroduced, referred to above, can have substituents other thanhydrogen, as for example, but without limitation, lower alkyl, chlorine,brornine, trifluoromethyl, or methylsulfonyl; such substituents do notinterfere with the course of the reactions here involved.

The following examples illustrate the best mode contemplated by theinventor of using the claimed processes of the invention and of themanner of making and using specific embodiments of the claimedcompositions of the invention.

EXAMPLE 1 To a suspension of 17.1 g. of 5-chloroanthranilic acid in 250ml. of chloroform, add with stirring, a solution of 20 g. ofacetoxyacetylchloride in 50 rnl. of chloroform. Heat the reactionmixture as necessary to maintain reflux, continuing the reuxing untilthe evolution of hydrogen chloride gas is complete, i.e., about 11/2hours. Allow to cool to precipitate 5-chloro-N-acetoxyacetylanthranilicacid (25 g.). On recrystallization from an alcohol-water mixture, theproduct has an M.P. 204-207" C.

AnalyszsCalculated for `C11H10C1NO5 (percent): C, 48.62; H, 3.71; N,5.16; C1, 13.05. Found (percent): C, 48.94; H, 3.63; N, 5.38; Cl, 13.3.

Prepare 5 chloro N p tolylsulfonoxyacetylanthranilic acid, M.P. 204-206C., from 7.0 g. of 5-chloroanthranilic acid and 12 g. ofp-toluenesulfonoxyacetyl chloride according to the procedure describedabove.

Analysis-Calculated for ClHmClNOS (percent): C, 50.07; H, 3.68; N, 3.65;Cl, 9.24; S, 8.35. Found (percent): C, 50.21; H, 3.75; N, 3.61; Cl, 9.5;S, 8.50.

Prepare 5 chloro N phenylsulfonoxyacetylanthranilic acid, M.P. 1834185"C., from 13 g. of 5-chloroanthranilic acid and 18 g. ofphenylsulfonoxyacetyl chloride according to the procedure describedabove (dmethoxyethane as solvent).

AnaZysis.-Calculated for CH12C1NO6'S (percent): C, 48.72; H, 3.27; N,3.75; Cl, 9.59; S, 8.67. Found (percent): C, 48.61; H, 3.13; N, 3.73;Cl, 9.7; S, 8.6.

EXAMPLE 2 Heat a mixture of 13.5 g. of5-chloroN-acetoxyacetylanthranilic acid and 130 ml. of acetic anhydrideon a steam bath for approximately 30 minutes at which time a clearsolution will have resulted. Concentrate the reaction mixture to 1/2 itsvolume, cool to obtain 5.5 g. of white solid6-chloro-2-acetoxymethyl-4H-3,l-benzoxazin- 4-one, M.P. 122-124 C.Further concentration of the ltrate resulting from separation of solidproduct, gives an additional 7.0 g., approximately.

Analysis.-Calculated for C11H3ClNO4 (percent): C, 52.09; H, 3.18; N,5.52; Cl, 13.98. Found: C, 52.30; H, 3.09; N, 5.62; Cl, 13.82.

EXAMPLE 3 To a suspension of 2.5 g. (0.01 mol) of 6-chloro-2-acetoxy-methyl-4H-3,1-benzoxazin-4-one in 25 ml. of anhydrous ether, adddropwise with stirring and chilling 15 ml. of ether containing0.0120.013 mol of phenylmagnesium bromide. Stir the reaction mixture atroom temperature for about Mt hour, then decompose the Grignard additionproduct and any excess Grignard reagent with excess 2 N hydrochloricacid. Separate the ether layer, partically concentrate, and chill toprecipitate 2- acetoxy-acetamido-5-chlorobenzophenone (1.4 g., M.P.121-123 C.).

EXAMPLE 4 To a suspension of 66.6 g. of 2-acetoxyacetamido-5-chlorobenzophenone in 550 ml. of ethanol, add with stirring a solutionof 8 g. of sodium hydroxide in 60 ml. of Water. Continue the stirringuntil all the reactants are dissolved and the solution is clear.

Add approximately 750 ml. of water to precipitate 2-hydroxyacetarnido-5-chlorobenzophenone. To purify, re-

6 crystallize from ethanol (55 g., 94% yield, M.P. 150- 152 C.).

Analysis.-Calsculated for C15H12C1NO3 (percent): C, 62.18; H, 4.18; N,4.84; iCl, 12.24. Found (percent): C, 62.29; H, 4.12; N, 4.72; Cl,12.30.

EXAMPLE 5 Prepare6-chloro-Z-p-tolylsulfonoxymethyl-4H-3,l-benzoxazin-4-one, M.P. 14C-142C., from 5-chloro-N-p-tolylsulfonoxyacetylanthranilic acid and 70 ml. ofhot acetic anhydride by the procedure described in Example 2.

EXAMPLE 6 Prepare 2-p-tolylsulfonoxyacetamido 5 chlorobenzophenone from3 g. of 6-chloro-2-p-tolylsulfonoxymethyl- 4H-3,1benzoxazin-4one and0.0065 mole of phenyl magnesium bromide by the procedure of Example 3.

Prepare 2-p-tolylsulfonoxyacetamido-5-chloro-2chlorobenzophenone from6chloro2-p-tolylsulfonoxymethyl- 4H-3,1benzoxazin4one and o-chlorophenylmagnesium bromide by the procedure of Example 3.

EXAMPLE 7 To a solution of 5.1 g. of2-p-bromophenylsulfonoxyacetamido-S-chlorobenzophenone in 15 ml.methylcellosolve, heated to 'C., add a solution of 10 g. ofhydroxylamine hydrochloride and 5 g. of sodium hydroxide in 20 ml. ofWater. Maintain the temperature at 95-90" C., for 15 minutes. Cool anddilute with water. Separate the precipitated product and recrystallizefrom benzene. There is obtained 2-hydroxyaminoacetamido-5chlor0benzophenone, M.P. 129-131 C.

Prepare 2 hydroxyaminoacetamido-5-chlorobenzophenone from2-p-tolylsulfonoxyacetamido-S-chlorobenzophenone by the proceduredescribed above.

The subject matter which the applicant regards as his invention isparticularly pointed out and distinctly claimed as follows:

1. The process for converting2-acyloxymethyl-6-chlor0-4H-3,1-benzoxazin-4-one wherein the acyl groupis selected from acetyl and phenylsulfonyl to2-acyloxyacetamido-5-chlorobenzophenone comprising: mixing oneequivalent of a phenyl magnesium halide with the benzoxazin-4-onedispersed in a liquid medium inert to the reactants; and, hydrolyzingthe resulting addition product in the presence of acid.

2. The process of claim 1 wherein the acyloxy group of the2acyloxymethyl substituent is phenylsulfonoxy.

3. The process of claim 1 wherein the acyloxy group of the2-acyloxymethyl substituent is acetoxy.

4. The process for preparing 2-acyloxyacetamido-5- chlorobenzophenonewherein the acyl group is selected from acetyl and phenylsulfonylcomprising: converting 5- chloroanthranilic acid toN-acyloxyacetyl-5-chloroanthranilic acid by mixing with acyloxyacetylhalide wherein the acyl group is selected from acetyl andphenylsulfonyl; cyclizing the compound so produced by heating in thepresence of a dehydrating agent to obtain2-acyloxymethyl-6-chloro-4H-3,1-benzoxaZin-4-one; converting the4H-3,1-benzoxazin-4one to the corresponding2-,acy1oxyacetamido-benzophenone by mixing with one equivalent of aphenyl magnesium halide; and, hydrolyzing the resulting addition productin the presence of acid.

References Cited UNITED STATES PATENTS 3,120,521 2/1964 Sternbach et al.260-244 BERNARD HELFIN, Primary Examiner L. DE CRESCENTE, AssistantExaminer U.S. Cl. X.R. 260-490, 289

